The present invention relates to a controlled release formulation for the drug diltiazem or its pharmaceutically acceptable salts thereof and a method for manufacturing a controlled release dosage formulation containing diltiazem or a pharmaceutically acceptable salt thereof as the active ingredient. More specifically, the present invention relates to a modified controlled release formulation of diltiazem that is designed to be administered to patients before bedtime and to release the diltiazem in a controlled release manner so that the time of maximum concentration of diltiazem in the patients blood stream occurs in the morning hours when the patient is waking, i.e. more than 8 hours after administration, preferably more than 9 hours after administration, and most preferably between 10 and 15 hours after administration. Such modified controlled release systems that are designed to release the active ingredient at a time when the patient is most in need of the drug has been referred to a “chronotherapy” or “chronotherapeutics” in the art.
Diltiazem hydrochloride, commonly referred to as diltiazem, is a benzothiazine derivative that blocks the influx of calcium ions in smooth and cardiac muscle and has few side effects. Diltiazem has been shown to be useful in alleviating symptoms of chronic heart disease, particularly angina pectoris, myocardial ischemia and hypertension. Diltiazem also has been shown to have activity against arrythmia and may be useful in treating congestive cardiac insufficiency, Raynaud's syndrome and peripheral and cerebral circulatory insufficiency.
Recent publications relating to once a day diltiazem treatments have indicated that the time of the day (i.e. morning or evening) at which a patient takes the medication can affect the patients response to the medication. See generally Administration-Time-Dependent Effects of Diltiazem on the 24-Hour Blood Pressure Profile of Essential Hypertension Patients, by Kohno et al., Chronobiology International, Vol. 14, No. 1, pp. 71-84 (1997) and The Influence of Time of Administration on the Pharmacokinetics of Once-A-Day Diltiazem Formulation: Morning Against Bedtime, by Thiffault et al., Biopharmaceutics & Drug Disposition, Vol. 17, pp. 107-115 (1996). These publications suggest that an administration schedule that allows the maximum amount of diltiazem in the patients blood stream to occur in the morning hours, i.e. between 7:00 AM and 11:00 AM is the optimum dosing schedule.
Diltiazem is sold commercially in extended release pharmaceutical dosage forms that attempt to maintain a therapeutic serum level of diltiazem and minimize the effects of missed doses of the drug caused by lack of patient compliance. Some of the commercial forms currently available are CARDIZEM CD®, CARTIA®, CARDIZEM LA®, TIAZAC®, TAZTIA®, and DILACOR XR®. The FDA's Approved Drug Products with Therapeutic Equivalents publication, commonly known as the “Orange Book” lists the following patents for some of the aforementioned extended release dosage forms of diltiazem: U.S. Pat. Nos. 4,894,240; 5,470,584; 5,439,689; 5,286,497; 5,364,620; 5,002,776; 5,529,791; 5,288,505; 4,839,177 and 5,422,123. Other patents that describe extended release forms of diltiazem and that are owned by the assignee of the present application are U.S. Pat. Nos. 5,508,040; 5,419,917; 5,567,441; 6,524,620 and 6,270,805. These products typically release the drug so the maximum blood concentration occurs about eight to eleven hours after administration.
CARDIZEM® LA is a commercially available form of chronotherapeutic diltiazem which has recently become available. It is believed that this product is described in WO 01/41744. The formulations described in the CARDIZEM® LA labeling and in WO 01/41744 appear to employ free diltiazem (not coated) and diltiazem beads (extended release coated diltiazem pellets) that are mixed with a hydrophobic or wax material to control the release of the diltiazem from the dosage form. This dosage form is complicated and difficult to manufacturer.
It is an object of the present invention to provide a novel once-a-day chronotherapeutic form of diltiazem formulation that is easy to manufacture and provides a maximum concentration of diltiazem in the patients blood system at a time greater than 8 hours, preferably greater than 9 hours, most preferably between 10 and 15 hours, after administration.